Conjugation of drugs to antibodies, either directly or via linkers, involves a consideration of a variety of factors, including the identity and location of the chemical group for conjugation of the drug, the mechanism of drug release, the structural elements providing drug release, and the structural modification to the released free drug. In addition, if the drug is to be released after antibody internalization, the mechanism of drug release must be consonant with the intracellular trafficking of the conjugate.
Antibody-drug conjugates (ADC, also known as immunoconjugates) have demonstrated considerable utility as anti-cancer agents. In an ADC, a therapeutic agent (also referred to as the cytotoxic drug or toxin) is covalently linked to an antibody whose antigen is expressed by a cancer or other proliferative cell (tumor associated antigen). The antibody, by binding to the antigen, delivers the ADC to the cancer site. There, cleavage of the covalent link or degradation of the antibody leads to the release of the therapeutic agent. On the other hand, while the ADC is circulating in the blood system, the therapeutic agent is inactive because of its linkage to the antibody. Thus, the therapeutic agent used in an ADC can be much more potent than ordinary chemotherapeutic agents because of its highly localized release.
While a number of different drug classes have been tried for delivery via antibodies, only a few drug classes have proved efficacious as antibody-drug conjugates, while having a suitable toxicity profile. One successful drug class includes analogs of FR901464, such as spliceostatin C and thailanstatin A, which are extremely potent inhibitors of eukaryotic RNA splicing. These compounds bind tightly to the SF3b subunit of the U2 snRNA subcomplex, an essential component of the spliceosome (Puthenveetil, S., et al., Bioconjugate Chem., 2016, 27:1880-1888).
U.S. Pat. Nos. 9,169,264 and 9,504,669 (both Subramanyam et al.) disclose spliceostatin-based compounds useful as payloads in ADCs and payload-linker compounds useful in connection with ADCs. The patents further disclose use of these compounds in the treatment of pathological conditions including cancer.